Physical and psychosocial stressors have been shown to compromise immune function. An individual's response to a stressor is manifested in physiological, hormonal, behavioral, and immunological changes. These stress-induced responses are initiated by the hypothalamus and translated into action by the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system. Products from these two systems (e.g., corticoid hormones and catecholamines) are able to modulate the activity of various immune effector cells directly. Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS), affecting approximately 1/2000 of the US population. The etiology of this disease is unknown, although viral infection in early adulthood is suspected as an initiating event followed by autoimmune-mediated demyelination. In common with other autoimmune diseases, stressful life events may precipitate both the onset and clinical relapses in MS patients. The current proposal examines the effect of stress on the pathogenesis of an animal model of multiple sclerosis, Theiler's virus-induced demyelination (TVID). Persistent infection of the CNS with Theiler's virus results in primary inflammatory demyelination which has proved to be an excellent model of MS. Current research indicates that chronic restraint stress during early infection with Theiler's virus results in high levels of glucocorticoids, immunosuppression, reduced immune cell infiltration into the CNS and consequently reduced viral clearance and increased mortality. This proposal seeks to determine the effect of stress on the ability of the host to mount an anti-viral immune response within the CNS and the effect of stress on the ability of a virus to establish a persistent infection in the CNS. Preliminary results also indicate that restraint stress during the later demyelinating phase of Theiler's virus infection modulates the clinical signs of disease. This phenomenon will be further investigated in order to determine how stress impacts on the immune system and subsequently alters the demyelinating disease process. The current application proposes to use the restraint stress paradigm to identify the neuroimmune mechanisms that underlie susceptibility to virus-induced demyelinating disease. Clarifying how environmental stressors influence an individual's vulnerability to autoimmune disease may increase our understanding of diseases such as multiple sclerosis and thus lead to the development of therapeutic regimens.